Antithrombotic activity of NSP-513, a novel selective phosphodiesterase 3 inhibitor, on femoral arterial thrombosis induced by physical stenosis and electrical current: Comparison of antithrombotic and hemodynamic effects

NSP-513, a novel potent and selective phosphodiesterase 3 (PDE 3) inhibitor , and cilostazol, a previously developed PDE 3 inhibitor, were compared wit h respect to antiplatelet, antithrombotic, and hemodynamic effects. In the in vitro antiplatelet aggregation studies, NSP-513 and cilostazol inhibited collagen-induced canine platelet aggregation with median inhibitory concen tration (IC50) values of 0.093 and 3.1 mu M, respectively, and inhibited ad enosine diphosphate (ADP)-induced canine platelet aggregation with IC50 val ues of 0.15 and 12 mu M, respectively. For ADP-induced platelet aggregation , the presence of prostaglandin E-1 (PGE(1); 3 and 10 nM) further decreased the IC50 values for NSP-513 to 0.11 and 0.032 mu M, respectively. In ex vi vo antiplatelet aggregation studies, orally administered NSP-513 (0.03-1 mg /kg) and cilostazol (50 mg/kg) inhibited collagen-induced canine platelet a ggregation. In an in vivo canine femoral arterial thrombosis model, intradu odenally administered NSP-513 (0.01-0.03 mg/kg) dose-dependently prevented thrombus formation without any changes in blood pressure, heart rate, or bl eeding time. In conscious dogs, NSP-513 at oral doses of greater than or eq ual to 0.3 mg/kg produced hemodynamic changes such as decreased blood press ure and increased heart rate and LVdP/dt(max). Thus the minimal hemodynamic ally effective dose of NSP-513 was 0.3 mg/kg, and the hemodynamic effects o f this dose were comparable to those of 50 mg/kg of cilostazol, In conclusi on, these data suggest that NSP-513 has in vivo selectivity for antiplatele t and antithrombotic activities over hemodynamic activity, and that the sel ectivity of NSP-513 is higher than that of cilostazol in dogs.